PXD072281-1

PXD072281 is an original dataset announced via ProteomeXchange.

Title	Molecular Glue Degraders of the RNA Binding Protein HuR to Treat BRAF-Mutant Colorectal Cancer
Description	BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all colorectal cancer (CRC) patients, and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as Encorafenib are ineffective due to MAP kinase pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, though approved therapies, results in short survival benefits and frequent treatment resistance and relapse1-3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumor growth, invasion, and therapy resistance. dHuR binds the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by Cryo-EM structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF mutant CRC tumors including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat refractory BRAF-mutant CRC patients.
HostingRepository	iProX
AnnounceDate	2025-12-21
AnnouncementXML	Submission_2025-12-22_00:36:09.584.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Luxiao Cui
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-22 00:35:46	ID requested
⏵ 1	2025-12-22 00:36:10	announced

Dataset with its publication pending

submitter keyword: molecular glue, Colo205

Yong Cang
contact affiliation	Shanghaitech University
contact email	cangyong@shanghaitech.edu.cn
lab head
Luxiao Cui
contact affiliation	Shanghaitech University
contact email	1799231058@qq.com
dataset submitter

iProX dataset URI